ABSTRACT
Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b(+) DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esam(hi) DC subset required lymphotoxin beta receptor signaling, proliferated in situ, and facilitated CD4(+) T cell priming. The Notch-independent Esam(lo) DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b(+)CD103(+) DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4(+) T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b(+) DC subsets in the spleen and intestine.
Subject(s)
Cell Differentiation , Dendritic Cells/cytology , Dendritic Cells/immunology , Intestines/immunology , Receptor, Notch2/metabolism , Signal Transduction , Spleen/immunology , Animals , Cell Differentiation/immunology , Cells, Cultured , Dendritic Cells/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Developmental , Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , Intestinal Mucosa/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Spleen/metabolism , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
Dendritic cells are critically involved in the promotion and regulation of T cell responses. Here, we report a mouse strain that lacks conventional CD11c(hi) dendritic cells (cDCs) because of constitutive cell-type specific expression of a suicide gene. As expected, cDC-less mice failed to mount effective T cell responses resulting in impaired viral clearance. In contrast, neither thymic negative selection nor T regulatory cell generation or T cell homeostasis were markedly affected. Unexpectedly, cDC-less mice developed a progressive myeloproliferative disorder characterized by prominent extramedullary hematopoiesis and increased serum amounts of the cytokine Flt3 ligand. Our data identify a critical role of cDCs in the control of steady-state hematopoiesis, revealing a feedback loop that links peripheral cDCs to myelogenesis through soluble growth factors, such as Flt3 ligand.
Subject(s)
Dendritic Cells/immunology , Membrane Proteins/immunology , Myeloproliferative Disorders/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Proliferation , Dendritic Cells/metabolism , Homeostasis/immunology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Myeloproliferative Disorders/metabolism , Syndrome , T-Lymphocytes, Regulatory/metabolismABSTRACT
Plasmacytoid dendritic cells (PDCs) represent a unique immune cell type specialized in type I interferon (IFN) secretion in response to viral nucleic acids. The molecular control of PDC lineage specification has been poorly understood. We report that basic helix-loop-helix transcription factor (E protein) E2-2/Tcf4 is preferentially expressed in murine and human PDCs. Constitutive or inducible deletion of murine E2-2 blocked the development of PDCs but not of other lineages and abolished IFN response to unmethylated DNA. Moreover, E2-2 haploinsufficiency in mice and in human Pitt-Hopkins syndrome patients was associated with aberrant expression profile and impaired IFN response of the PDC. E2-2 directly activated multiple PDC-enriched genes, including transcription factors involved in PDC development (SpiB, Irf8) and function (Irf7). These results identify E2-2 as a specific transcriptional regulator of the PDC lineage in mice and humans and reveal a key function of E proteins in the innate immune system.
Subject(s)
Dendritic Cells/immunology , Nerve Tissue Proteins/immunology , TCF Transcription Factors/immunology , Adolescent , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Child , Child, Preschool , DNA-Binding Proteins , Dendritic Cells/metabolism , Humans , Hyperventilation/immunology , Immunity, Innate , Intellectual Disability/immunology , Interferons/immunology , Mice , Syndrome , Transcription Factor 4 , Transcription Factor 7-Like 2 Protein , Transcription FactorsABSTRACT
Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch-RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8(-) DC subset and reduced the frequency of cytokine-secreting CD8(-) DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J-deficient splenic CD8(-) DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8(-) DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch-RBP-J signaling controls the maintenance of CD8(-) DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
